Tumorigenesis is a multi-step process wherein a causal relationship exists between accumulation of genetic abnormalities and aggressive clinical behavior of tumor cells (Fearon et al., 1990, Cell 61:759-767; Callfano et al., 1996, Cancer Res 56:2488-2492). In many tumors, amplification of critical growth-inducing genes is observed, coupled with deregulated expression of G1 cyclins and their cognate cdk partners (Lammie et al, 1991, Oncogene 6:439-444; Motokura et al., 1991, Nature 350:512-515).
Distinct complexes are formed between cyclins and one or more cognate cyclin dependent kinases (cdk's) at different phases of the cell cycle, and activation of the cognate kinases occurs following complex formation. Progression of cells through the late G1 phase of the cell cycle is controlled by G1 cyclins, including D and E type cyclins and their cognate cdk's (Sherr, 1994, Cell 79:551-555). Phosphorylation of the retinoblastoma gene product (Rb) and related gene products facilitates entry into S phase. The D type cyclins are known to form complexes with either cdk4 or cdk6 (Baldin et al., 1993, Genes Develop. 7:812-821).
Expression of G1 cyclins and their cognate cdk partners is often deregulated in human tumor cells. Overexpression of cyclin D1 can shorten the G1 interval of the cell cycle, and thereby reduce cell size and/or transform cells, both in vitro and in vivo (Jiang et al., 1993, Oncogene 8:3447-3457; Lovec et al., 1994, Oncogene 9:323-326).
Primary cutaneous lymphomas are among the more common presentations of extra-nodal non-Hodgkins lymphomas (NHLs). NHLs include adult T-cell leukemia/lymphoma (ATLL) and cutaneous T-cell lymphoma (CTCL). The etiologic agent of ATLL, HTLV-1, has been known for years. In contrast, the molecular pathogenesis of CTCL, the most frequent type of cutaneous lymphoma, is not well characterized at present. A recent report demonstrated rearrangement of the tal-1 and lyt-10 genes in a small subset of CTCL cells, but no consistent molecular lesions were detected (Neri et al., 1995, Blood 86:3160-3172).
Development of effective anti-cancer or anti-tumorigenic treatments would be facilitated by identification of one or more genes, mal-expression of which is associated with the onset or progression of tumorigenesis. The present invention provides the identity and the coding sequence of such a gene.